Throughout this application various publications are referenced, many in parenthesis. Full citations for these publications are provided at the end of the Detailed Description. The disclosures of these publications in their entireties are hereby incorporated by reference in this application.
It is estimated that ten percent of persons older than 65 years of age have mild to severe dementia. Alzheimer's disease (AD) is the most common cause of chronic dementia with approximately two million people in the United States having the disease. Although once considered a condition of middle age, it is now known that the histopathologic lesions of Alzheimer's disease (i.e., neuritic amyloid plaques, neurofibrillary degeneration, and granulovascular neuronal degeneration) are also found in the brains of elderly people with dementia. The number of such lesions correlates with the degree of intellectual deterioration. This high prevalence, combined with the rate of growth of the elderly segment of the population, make dementia (and particularly AD) one of the most important current public health problems.
Deposition of cerebral amyloid is a primary neuropathologic marker of Alzheimer's disease. The amyloid is composed of a 40-42 amino acid peptide called the amyloid beta protein (A.beta.) (Glenner and Wong, 1984). Amyloid deposits in AD are found mainly as components of senile plaques, and in the walls of cerebral and meningeal blood vessels (Robakis and Pangalos, 1994).
Molecular cloning showed that A.beta. comprises a small region of a larger amyloid precursor protein (APP) (Robakis et al., 1987; Weidemann et al., 1989). Briefly, this is a type I integral membrane glycoprotein having a large extracytoplasmic portion, a smaller intracytoplasmic region, and a single transmembranous domain. APP undergoes extensive post-translational modifications (Pappolla and Robakis, 1995; Robakis and Pangalos, 1994) prior to the secretion of its N-terminal portion (Sambamurti et al., 1992; Robakis and Pangalos, 1994). Physiologic processing of APP involves cleavage within the A.beta. sequence by an unidentified enzyme, alpha-secretase (Anderson et al., 1991). Smaller quantities of APP molecules are cleaved at two other sites that could potentially produce amyloidogenic secreted or membrane bound APP (Robakis and Pangalos, 1994). A.beta. is also produced during normal cellular metabolism (Haass et al., 1992; Shoji et al., 1992).
There is some controversy as to whether amyloid causes AD; however, three main lines of evidence have strengthened the amyloid hypothesis. The first piece of evidence is provided by the identification of several point mutations within the APP gene. These mutations segregate within a subgroup of patients afflicted with a familial form of the disorder and thus suggest a pathogenetic relationship between the APP gene and AD (Chartier-Harlin et al., 1991; Kennedy et al., 1993). Secondly, amyloid deposition temporally precedes the development of neurofibrillary changes (Pappolla and Robakis, 1996) and this observation is also consistent with a link between amyloid and neuronal degeneration. Finally, it has been shown that A.beta. is toxic to neurons (Yankner et al., 1990; Behl et al., 1992; Behl et al., 1994; Zhang et al., 1994), a finding that also strengthened the hypothesis that the amyloid peptide may contribute to the neuronal pathology in AD.
The finding that A.beta. has neurotoxic properties has provided a possible connection between amyloid accumulation and neurodegeneration. After a number of controversial reports, studies from several laboratories have now corroborated this observation and demonstrated that the effects of the peptide are dependent on aggregation (Busciglio et al., 1992; Pike et al., 1993), time of exposure, osmolarity, pH and concentration (Burdick et al., 1992; Pik et al., 1993). The mechanism of toxicity is not totally understood. In addition to free-radicals, increased sensitivity to excitotoxicity (Copani et al., 1995) and/or disruption of Ca.sup.2+ homeostasis (Mattson et al., 1992; Mattson et al., 1993; Le et al., 1995; Mark et al., 1995) seem to be involved. The magnitude of the damage contributed by each of these factors and the extent of their interaction are unresolved issues (Busciglio et al., 1993; Mattson, 1994; Weiss et al., 1994; Copani et al., 1995). Because of the close association between aging and AD and the similarities in the neuropathology of both conditions, oxidative stress has been proposed to play a role in the pathogenesis of AD lesions.
Several investigators demonstrated that oxygen free-radicals (OFRs) are related to the cytotoxic properties of A.beta. (Behl, 1992; Behl, 1994; Harris et al., 1995; Butterfield et al., 1994; Goodman and Mattson, 1994). Such findings are important, since markers of oxidative injury are topographically associated with the neuropathologic lesions of AD (Pappolla et al., 1992; Furuta et al., 1995; Smith et al., 1995; Pappolla et al., 1996). Because of these observations, antioxidants have been proposed as potential therapeutic agents in AD (Mattson, 1994; Hensley et al., 1994; Pappolla et al., 1996).
Interestingly, melatonin exhibits antioxidant properties (Reiter, 1995), but, in contrast to conventional antioxidants, this hormone has a proposed physiologic role in the aging process (Pierpaoli, 1991; Pierpaoli et al., 1991) and decreased secretion of melatonin with aging is documented (Iguchi et al., 1982; Dori et al., 1994). There are reports of more profound reductions of melatonin secretion in populations with dementia than in non-demented controls (Souetre et al., 1989; Mishima et al., 1994). It has been suggested that altered secretion levels of the hormone may partially reflect the loss of daily variation in the concentration of melatonin in the pineals of elderly individuals and AD patients (Skene et al., 1990). These facts regarding melatonin are in sharp contrast with conventional anti-oxidants which despite their reported cytoprotective characteristics have no comparable correlates with the pathophysiology of human aging.
The effects of melatonin are complex. In addition to its OFR scavenging properties, melatonin interacts with calmodulin (Benitez-King and Anton-Tay, 1993), microtubular components (Benitez-King and Anton-Tay, 1993), and is reported to increase the activity of the intrinsic cellular antioxidant defenses (Huerto-Delgadillo et al., 1994).
A need continues to exist for methods of treating AD.